In a comprehensive and provocative report in this issue of Blood, with findings that were not necessarily expected, Hughes and colleagues report on the immune reconstitution that occurs as a consequence of the deepening remission achieved by patients with chronic myelogenous leukemia (CML) on tyrosine kinase inhibitors (TKIs). A significant fraction of patients with CML treated with BCR-ABL TKI achieve long-term remissions and maintain this state even after stopping the TKI. Why is this? Although the TKI itself may be contributing to this immune restoration, it is not entirely responsible as best effects are observed in those patients no longer on these drugs.1

The authors examined the immunophenotype and content of cells in a large series of patients with CML, beginning with diagnosis and moving through cohorts at different stages and depth of remission on TKIs, concluding with patients off of therapy and in remission. In these cohorts, the decreasing level of BCR-ABL correlated directly with the fall in levels of regulatory T cells, myeloid-derived suppressor cell, and PD-1 expression, along with their associated immunosuppressive functions. At the same time, natural killer cell and T-cell function improved; in particular, strong responses to leukemia-associated antigens, such as PRAME, WT1, PR3, and BMI-I, were noted. Responses directed to bcr/abl proteins were not examined, but specific responses to the underlying oncogenic product have been difficult to demonstrate. The cause of this immune restoration may well be the reduction in the massive immunosuppressive tumor burden, often upwards of 1 trillion CML cells at diagnosis. Furthermore, it is not yet clear whether the restoration of the antigen-specific immune response is a cause, or an effect, of the deepest remissions achieved.

The findings have important implications for therapy and the immune biology of CML. The authors ask whether the knowledge of immune recovery and its implied involvement in maintenance of remission could be used to predict which patients might successfully stop therapy. Perhaps more important is to ask whether further augmentation of the immune response to the CML cells might bring a larger fraction of patients on TKIs more rapidly into long-term unmaintained remission or even cure. These outcomes might be accomplished most immediately and crudely with a marketed checkpoint blockade antibody, or by use of a nonspecific immunostimulant such as interferon. More elegantly, and specifically, might be to treat these patients with a more selective agent that would further direct the immune system to leukemia antigens PR1 or stem cell antigens such as WT1 or PRAME. This treatment might be a vaccine2⇓⇓-5 or a T-cell receptor mimic antibody6⇓-8 or an engineered T cell.9,10

In a time when immunotherapy is making great progress in hematologic cancers, and more surprisingly, in subsets of refractory solid tumors, it is especially encouraging to see possible immunological mechanistic explanations for the benefits of nonimmunologic small molecule therapies for CML, a disease that in 3 decades has moved from a relentlessly fatal illness to a chronic, and possibly curable, disease.

Footnotes

Conflict-of-interest disclosure: D.A.S. has invented and Memorial Sloan Kettering Cancer Center has licensed a WT1 vaccine to Sellas Life Sciences.